Portions of this invention were made with grants from the National Cancer Institute CA35329 and the National Science Foundation, DMB87-15954. The United States Government may have certain rights in this invention.
.alpha. 1,3-L-fucosyltransferases have been found to be elevated in sera of many individuals diagnosed with solid tumors such as those of ovarian cancer, stomach cancer, lung cancer, liver cancer, colon cancer, pancreatic cancer, lingua cancer, and cancer of the larynx and many others. Reference may be had to "Elevated Activities of Serum .alpha. (1.fwdarw.3)-L-Fucosyltransferase in Human Cancer", Yazawa et al., Journal of Tumor Marker Oncology, 1989, Vol. 4, No. 4, pp. 355-361 and "Fucosyltransferases: Differential Plasma and Tissue Alterations in Hepatocellular Carcinoma and Cirrhosis", Hutchinson et al , Institute of Liver Studies, Kings College Hospital and School of Medicine and Dentistry, Denmark Hill, London, UK, 1990 and "Changes in Fucose Metabolism Associated with Heavy Drinking and Smoking: A Preliminary Report", Thompson et al , Clinica Chimica Acta, 201: 59-64 (1991); and "Tumor-related Elevation of Serum (.alpha.1.fwdarw.3)-L-Fucosyltransferase Activity in Gastric Cancer", Yazawa et al , J. Canc. Res. Clin. Oncol., 115: 451-455, 1989; all of which are incorporated herein by reference. This enzyme thus appears useful as a diagnostic marker for cancer.
The expression of mono, di and trimeric x-determinants in glycolipids of colon carcinoma was shown to be due to the retrogenetic expression of type 2 chain precursors (Gal.beta.1, 4 Glc NAc.beta.) that were not found in normal adult colonic epithelial cells. This implies that the type of the precursor restricted the fucosyltransferase involved to transfer fucose to the C-3 position of GlcNAc. Further, human colonic adenocarcinoma Colo 205 cells, in contrast to human small cell lung carcinoma NCI-H69 cells and lung carcinoma PC 9 cells (9,10), transferred fucose in .alpha.1,4 linkage to lacto-series type 1 chain structures (Gal .beta.1,3 Glc NAc.beta.) and in .alpha.1,3 linkage to type 2 chain structures. A report on the separation of .alpha.1,3 and .alpha.1,4 fucosyltransferase activities of human milk on Sephacryl S-200 column indicated that neither enzyme fraction was absolutely specific for type 1 or 2 chain acceptors. It becomes thus evident that the expression of .alpha.1,3 and .alpha.1,4 fucosylated lacto-series carbohydrate chains involves fucosyltransferases exhibiting varying degrees of substrate specificity and differing cell and tissue distribution (14-16). Carbohydrates containing the type 2 chain Gal.beta.1, 4GlcNAc.beta. and the corresponding NeuAc.alpha.2, 3Gal.beta.1, 4GlcNAc.beta.-type structures have been used for the assay of .alpha.1,3-L-fucosyltransferases. It has been shown that 2'-fucosyl LacNAc is a preferred substrate for .alpha.1,3-L-fucosyltransferase of human neuroblastoma cells. Apart from the known sulfated glycoconjugates such as mucins and glycolipids, sulfate groups have only recently been identified in some glycoproteins. The sulfate group in glycolipids is generally linked to a position, otherwise occupied by a sialyl residue. It has been found that SO.sub.4 .fwdarw.3Gal.beta.1, 4GlcNAc is a terminal sequence of the asparagine linked carbohydrate chain of porcine thyroglobulin.
Adhesion of circulating leukocytes to the vascular endothelium during inflammation is mediated in part by their interaction with the endothelial-leukocyte adhesion molecule ELAM-1, a member of the LELAM family of adhesion molecules, and there is evidence that the interactions may be regulated by certain .alpha.(1-3) fucosyltransferases.
See "ELAM-1-Dependent Cell Adhesion to Vascular Endothelium Determined by a Transfected Human Fucosyltransferase cDNA", Lowe et al., Cell, Vol. 63, 475-484, Nov. 2, 1990.
It is therefore desirable to have a compound which will bind to .alpha. 1,3-L-fucosyltransferases with sufficient specificity so that the .alpha. 1,3-L-fucosyltransferases can be easily selectively detected both for purposes of investigation and for purposes of diagnoses and predication of disease. Further, such a binding compound can affect the activity of .alpha. 1,3-L-fucosyltransferases thus desirably slowing or stopping diseases in which it is implicated. Such a binding compound can further bind to organic structures which mimic the structure of .alpha.1,3-L-fucosyltransferases, at least insofar as binding sites are concerned.
Further, such a binding compound may be attached to auxiliary compound structures such as toxins or antineoplastic compounds to carry such auxiliary structures to the .alpha. 1,3-L-fucosyltransferases or organic structures which mimic them.
A number of acceptors for fucosyltransferases are known, unfortunately such acceptors do not distinguish .alpha. 1,3-L-fucosyltransferases from other fucosyltransferases as well as desired. Such acceptors are also not as sensitive as desired and do not have an affinity as high as desired.
Examples of compounds which, to a more or less extent, may act as acceptors for fucosyltransferases are 2'methyl lactosamine (2'methyl Lac NAc), 2'-fucosyl Lac NAc, 3-fucosyl Lac NAc, and the .beta.-benzyl glycosides of Lac NAc, 2'methyl Lac NAc, Gal.beta.1 and 3 GalNAc.